Acylation of hindered tertiary alcohols proceeds with difficulty because of both the reduced reactivity of the tertiary alcohol to acylation and the hindered nature of the hydroxyl group.
In 17.alpha.-hydroxy steroids such as the corticoids and 17.alpha.-hydroxyprogesterones, the 17.alpha.-hydroxy group is a tertiary alcohol and is very hindered. Acylation of the 17.alpha.-hydroxy group of the corticoids and 17.alpha.-hydroxyprogesterones requires vigorous conditions and is generally accompanied by various undesirable side reactions.
D-homo rearrangement occurs under both basic (e.g., acetic anhydride-pyridine) or acidic (e.g., acetic anhydride-p-TSA) acylation conditions. See D. N. Kirk and M. P. Hartshorn, "Reaction Mechanisms," Elsevier Publishing Co., N.Y., 1968, page 294; E. P. Olweto et al., J. Am. Chem. Soc., 79, 3594 (1957); N. L. Wendler et al., ibid 78, 5027 (1956); and D. K. Fukushima et al., ibid 77, 6585 (1955).
Corticoids and 17.alpha.-hydroxyprogesterones both contain the .DELTA..sup.4 -3-ketone functionality in ring A. This .alpha.,.beta.-unsaturated ketone undergoes enol acylation at C-3 during the usual acid catalyzed acylation at C-17. See U.S. Pat. Nos. 3,678,082; 2,753,360, Example 2; and U.S. Pat. No. 3,061,616, Example 8 as well as C. Djerassi et al., J. Am. Chem. Soc., 77, 3826 (1955) and R. Vitlotti et al., ibid, 81, 4566 (1959). The C-3 acylate must then be hydrolyzed to obtain the .DELTA..sup.4 -3-keto ring A structure. These extra steps are certainly undesirable in any event, but with the corticoids the 3-enolization produces additional problems. The acylated product (3,17,21-triacylate) upon hydrolysis condition sufficient to hydrolyze the C-3 acylate also hydrolyzes the C-21 acylate. When this occurs it is followed by migrations of the C-17 acylate to C-21 with further hydrolysis, etc.
The ring A functionality, .DELTA..sup.1,4 -3-keto undergoes irreversible dienone phenol rearrangement under acidic conditions (see Kirk, ibid, page 277) producing unwanted side product.
Another undesirable side reaction occurs with C-17 allylic and propargyl alcohols which eliminate under acidic acylation conditions.
U.S. Pat. No. 3,998,701 claims a process for preparing steroidal 17-esters of the corresponding 17.alpha.,21-dihydroxy 21-phosphate. This process by virtue of the requirement for a 21-phosphate is limited to corticoids and is not applicable to 17.alpha.-hydroxyprogesterones. An additional disadvantage to this process is that after C-17 acylation the C-21 phosphate group must be hydrolyzed enzymatically.
British Pat. No. 868,303, Example V, discloses the preparation of the caproate ester of 6.alpha.-methyl-17.alpha.-hydroxyprogesterone using caproic anhydride and p-TSA. This process took 60 hours and required heating on a steam bath.
A. J. Fatiadi, Carbohyd. Res., 6, 237 (1968) reported using acetic anhydride and anhydrous phosphoric acid to acylate various alcohols including, " . . . sterically hindered secondary alcohols, and tertiary alcohols; . . . ". Table I on page 238 disclosed the various alcohols which were acylated--none are tertiary alcohols. As stated in the first sentence of Fatiadia's article, he was looking to find an acylation agent for enolic compounds. The 17.alpha.-hydroxy group, in the steroids of the present invention, is not an enolic group.
U.S. Pat. No. 3,678,082 claims a process for acylating 17.alpha.-ethynyl-17.beta.-hydroxy steroids by use of 4-(dimethylamino)pyridine. The catalyst in U.S. Pat. No. 3,678,082 is an organic base whereas the catalyst in the present invention is a phosphoric acid-type compound.
Offenlegungsschrift No. 2,055,221 discloses a process for acylating 17.alpha.-hydroxypregnanes in high yields by use of an anhydride or acid chloride with anhydrous stannic chloride (SnCl.sub.4).